Macrophage-associated prognostic modeling uncovers immunotherapy response mechanisms and defines HAGHL as a novel oncogenic driver in breast cancer

Background Macrophage−related genes (MRGs), a group of pivotal regulators governing macrophage differentiation, polarization, and function, have increasingly been recognized as critical modulators in tumor progression and immune evasion. However, the molecular expression profiles of MRGs and their intricate relationships with the immune microenvironment in breast cancer (BRCA) remain insufficiently investigated. Methods We first used bulk RNA sequencing and single-cell RNA sequencing data from the TCGA and GEO databases, we analyzed the molecular expression patterns and clinical relevance of MRGs in BRCA. A prognostic model was developed using these genes, and the variations in the immune microenvironment between the high-risk and low-risk groups were evaluated. Additionally, the model’s predictive ability for immunotherapy response was assessed. Finally, we conducted in vivo and in vitro experiments to study the biological functions of HAGHL. Results Multi-omics analysis identified a group of MRGs with prognostic value, leading to the successful development of a model that stratified BRCA patients into high- and low-risk categories. The model demonstrated high accuracy in predicting patient survival. Immune microenvironment-related analysis revealed significant differences between risk groups, and the model effectively predicted responses to immunotherapy. CellChat analysis suggested potential macrophage pathways in BRCA. Our results also show that HAGHL, as a carcinogenic factor in BRCA, knockdown can inhibit the proliferation and invasion of BRCA cells. Conclusions We developed a prognostic model based on MRGs, which holds promise for predicting outcomes in BRCA patients and responses to immunotherapy. Our findings offer new insights and potential guidance for personalized treatment strategies in BRCA. Additionally, we identified HAGHL as a potential oncogene, laying the groundwork for future research.